The lack of a suitable hemocompatibility of elastomeric materials to be used in the preparation of cardio-vascular prostheses is the major problem to be solved in the study and application of prosthetic materials in the cardio-vascular field. The contact of an extraneous surface with blood always triggers coagulation mechanisms; as a consequence, a therapy with anticoagulants is combined with a prostheses implant, with a subsequent risk of onset of side effects, such as bleeding. The search for non thrombogenic surfaces is one of the means now under study for the resolution of the problem (T. Akutsu, Artificial Heart, Igaku Shoin Ltd., Tokyo, (1975); F. W. Hastings in Advances in Chemistry Series, ed R. F. Gould, (1987)), by means of biological activity (adhesiveness by stimulating the growth of endothelial cells) or biochemical (for example heparin release ability, through a controlled release mechanism, or keeping this anticoagulant molecule stably, without reducing its activity (M. C. Tanzi, B. Barzaghi, R. Anouchinsky, S. Bilenkis, A. Penhasi, D. Cohn "Grafting reactions and heparin adsorbtion of polyamidoamine-grafted polyurethane amides" Biomaterials, 13, 425-431 (1992)).
In order to avoid unwanted side effects, biocompatibility is a fundamental requirement of an extraneous material when the latter is contacted with human organism. On the other side, there are a great number of biomedical applications, which provide the use of synthetic polymers. These polymers can delay metabolism or excretion of drugs, which otherwise would require repeated or frequent administrations. The action of these polymers occurs through the formation of covalent bonds having controlled stability in biological environment, or, alternatively the polymers are the constituents of systems for the controlled release of drugs, by physical absorption and subsequent release. Prosthetic devices, among which vascular grafts made with synthetic polymers, have been used for more than 40 years; and now design and construction of artificial organs, such as heart, are at reach.
In the most part of the cases disclosed in the past literature, the bond between polymer and heparin was not established directly, but through preliminary adsorption of quaternary ammonium salts on the polymeric material and subsequent complex formation with heparin on the modified material.
This heparinization method showed several drawbacks, which made difficult its application in living organisms in the long period. In fact, ammonium salts tend to deadsorb; further, the compounds containing quaternary ammonium groups generally showed haemolytic activity and affected platelets.
Subsequent studies led to the discovery of polymers containing tertiary amino groups regularly distributed along the macromolecular chain. These last polymers, polyamidoamines (PAA) are capable of linking to heparin stably. Linear polymers of the polyamidoamine type, obtained by addition of polyaddition of primary monoamines or secondary diamines to bisacrylamides, have been widely disclosed in the past (F. Danusso, P. Ferruti, G. Ferroni, La Chimica and l'Industria, 49, 271, (1967); F. Danusso, P. Ferruti, G. Ferroni, La Chimica and l'Industria, 49, 453, (1967); F. Danusso, P. Ferruti, La Chimica and l'Industria) as compounds capable of complexing heparin stably (M. A. Marchisio, T. Longo, P. Ferruti, Experientia, 29, 93, (1973); P. Ferruti, E. Martuscelli, L. Nicolais, M. Palma, F. Riva, Polymer, 18, 387, (1977); P. Ferruti in (IUPAC) Polymeric amines and ammonium salts, E. J. Goethals Ed., Pergamon Press, Oxford and New York, 305-320, (1980); P. Ferruti, M. A. Marchisio, Biomedical and dental application of polymers, C. G. Gebelein and F. Koblitz Eds., Plenum Publ. Co., New York, 39-57, (1981)) and to assure a natural anticoagulant activity to the surfaces of the materials on which they were grafted or inserted (R. Barbucci et 25 al., Biomaterials, 10, 299-308, (1989); M. C. Tanzi, M. Levi, Journal of Biomedical Materials Research , 23, 863 (1989)).
Heparin is a mucopolysaccharide containing carbonyl and sulphonyl groups, which behaves as a polyanion in aqueous solution at physiological pH. The ability of PAA of giving stable bonds with heparin is due to the interaction of ionic and electrostatic type that occurs between the negative charges of heparin and the amino groups of the PAA, which are protonated at physiological pH. Accordingly, new materials have been obtained, wherein the polyamidoamino segments were linked to segments of conventional polymers (for example styrene) with the purpose of obtaining materials having good mechanical properties and physico-chemical characteristics such as to turn out to be, after to treatment with heparin, permanently non-thrombogenic, therefore usable for the manufacture of artificial prostheses.
The main drawback of PAA and similar polymers is due to non-uniformity of molecular weight and to the difficulty of obtaining terminal groups all of the same kind. Accordingly, PAA are not suitable for use as macromonomers in the reproducible synthesis of polymers.
Polyurethanes are polymeric materials containing the urethane group --NH--CO--O-- in the macromolecular chain. These materials, according to their composition and structure, can exist in linear form (thermoplastic polyurethanes), cross-linked (thermosetting polyurethanes) and expanded (urethane foams).
Thermoplastic polyurethanes (Lilaoniktul, S. L. Cooper, "Properties of Thermoplastic Polyurethanes Elastomerics", Advances in Urethanes Sciences and Technology, K. C. Frisch, S L Reegen, 7) are linear copolymers of the --AnBm-- type, wherein An (soft segments) are generally of the polyester, polyether or polyalkyldiol type, with a molecular weight ranging between 600 and 3000. Hard segments (Bm) are formed by the parts of the macromolecular chain deriving from the reaction of an aromatic or aliphatic diisocyanate with a diol or a low molecular weight diamine (chain extender).
Thermoplastic polyurethane elastomers are then formed by segments of two structural entities having different characteristics within the same polymeric chain. At working temperature, one of the two components has flexibility properties (soft segment), whereas the second unit has a rigid nature either glass or hemicrystalline (hard segment). Due to incompatibility between the two components, these materials are characterised by a separation of phases in the solid state; the resulting two-phase structure is formed by aggregates or domains of hard segments dispersed in the elastomeric matrix of the soft segment.
Hard segments, dispersed in a matrix of soft segments, act as reinforcing particles and behave as physical cross-linking sites, which are reversible at high temperatures, giving the material elastomeric characteristics. Further, these materials can undergo typical processing of the polymeric materials; once cooled they behave again as chemically cross-linked rubbers.
The driving force for the segregation in domains is the chemical incompatibility between the soft and hard segments. Factors affecting the phase separation grade include intermolecular hydrogen bond, copolymer composition, solubility of hard segments with respect to soft segments, crystallizability of each of the two segments, manufacturing method and thermal and mechanical history.
The presence of a high number of hydrogen bonds is a typical characteristic of polyurethanes. Recent studies (Wilkes, J. A.; Emerson, J. Applied Phys. 47, 4261 (1976); W. Seymour, G:M: Estes, S. L. Cooper, Macromolecules, 3, 579, (1970)) stressed out that the separation grade affects the quantity and the type of hydrogen bond, not the contrary; the higher is the separation, the higher is the quantity of interurethane hydrogen bonds that forms.
Biomedical application of thermoplastic polyurethanes
Polyurethanes have found wide use in the creation of short term biomedical devices (catheters, endotracheal tubes, cannulas), but also for the production of permanent implants (intraaortic balloons, artificial ventricles, vascular prostheses) because they have good mechanical properties, very good abrasion and flexing resistance, good bio- and haemocompatibility, they are self-lubricating and easily processible.
Synthesis of thermoplastic segment-polyurethanes
The most important reaction for the synthesis of polyurethanes is the addition on the C.dbd.N bond. The reaction advances with a nucleophilic attack on the carbon atom of the isocyanate group by an alcohol, with formation of a urethane group --NH--CO--O--. The synthesis of polyurethanes is based on reactions occurring between the isocyanate group (--NCO) and a nucleophilic group (NH or OH) present in many compounds such as for example amines and alcohols. In the case of amines, urea bonds are formed (NH--CO--NH) and poly-urea-urethanes are so obtained.
Cross-linked polyurethanes are obtained by using at least a reactant having functionality higher than two, typically a triol or a tetraol. Linear polyurethanes are obtained starting from polydiols and bifunctional isocyanates.
Thermoplastic segment-polyurethanes can be prepared with two different procedures:
a single step process, with a direct reaction between diisocyanate and diol (and/or diamine) PA1 a two-step process, more used than the former in biomedical field: in a first step diisocyanate and polyol are reacted, forming a prepolymer, subsequently the obtained macromonomer is reacted with the chain extender, whereby a high molecular weight polymer is produced. PA1 reaction between diisocyanate and water, leading to the formation of an amine with release of carbon dioxide PA1 reaction between diisocyanate and urethane groups, leading to the formation of allophanates (cross-linking). It occurs particularly at high temperatures PA1 reaction between diisocyanate and ureic groups, thus forming biurets PA1 reaction between aromatic diisocyanates (in particular conditions), forming dimers PA1 reaction between aliphatic or aromatic diisocyanates, giving trimers.
During the polymerisation, also the following unwanted side reactions can occur (J. H. Saunders, K. C. Frisch, Polyurethanes Chemistry and Technology, Interscience Publishers):
The most used catalysts are tertiary amines or organometallic compounds, in particular those containing tin (Brunette, S: L: Hsu, W: J. Macknight, Macromolecules, 15, 71, (1982).
Tin organometallic compounds specifically catalyse the reaction between isocyanate and hydroxyl; accordingly they should be preferred to the amines for the production of elastomeric polyurethanes. Both tertiary amines and tin-organometallic compounds are cytotoxic (M. C. Tanzi, P. Verderio, Lampugnani et al., "Cytotoxicity of some catalysts commonly used in the synthesis of copolymers for biomedical use", J. Mat. Science: Mats. In Medic., 5, (1994)). It is therefore necessary to carry out a careful purification after the synthesis of the copolymer if its use in biomedical field is foreseen.
Diisocyanates
The most commonly used diisocyanates are the aromatic ones, in particular 2,4-toluendiisocyanate (TDI) and 4,4'-methylene-bis-phenyldiisocyanate (MDI).
The use of aliphatic diisocyanates, among which 1,6-hexamethylenediisocyanate (HDI), trans-1,4-cyclohexyldiisocyanate (CHDI), 4,4'-methylene-bis-cyclohexyldiisocyanate (HMDI) (the hydrogenated analogous of MDI), is less common.
Polyurethanes obtained from aromatic diisocyanates tend to form intermolecular bonds stronger than those formed between polyurethanes obtained with aliphatic diisocyanates (Stokes, J. Biomat. Appls. 3, 248 (1988) M. Szycher, J. Biomater. Appl., 3, 383 (1988)), showing a higher aptitude to the semicrystalline form. On the contrary, hard segments containing aliphatic diisocyanates not always have the possibility to crystallise, in fact, both HMDI and CHDI have different conformational isomers, which perturb crystallinity of the hard segments.
Since more crystalline hard segments help more phase separation in the copolymer, mechanical properties of aromatic polyurethanes are better than those of aliphatic polyurethanes; moreover the aromatic compounds are more reactive than the aliphatic ones, allowing to use lower doses of or eliminating the catalyst during the synthesis.
The advantage given by aliphatic diisocyanates is that the obtained polyurethanes do not become yellow, when exposed to light. The unwanted phenomenon of yellowing, occurring when aromatic diisocyanates are used, can be prevented by adding antioxidant agents, which must be however avoided in the case of implantable devices.
In-vivo studies (Stokes, J. Biomat. Appls. 3, 248 (1988); M. Szycher, J. Biomater. Appl., 3, 383 (1988)) demonstrated the relative stability of aromatic polyurethanes with respect to the aliphatic ones. (Christ, S. Y. Buchen, D. A. Fencil, P. Knight, K. D. Solomon and D. J. Apple, J. Biomed. Mat. Res., 26, 607 (1992)). Further, aromatic polyurethanes show a better flex fatigue.
The cancerogenic activity of possible release products, coming from aromatic polyurethanes, is still an unsolved problem. At the present state of the art, it is not sure that aromatic polyurethanes release carcinogenic substances in man; however part of the scientific research is investigating the possibility to obtain aliphatic polyurethanes with improved mechanical properties.
Macroglycols: polyester, polyether, polycarbonate
Polyester and polyether diols are the most commonly used macroglycols for the synthesis of polyurethanes for biomedical applications, in particular polytetramethylene oxide), even if recently new types of macroglycols with higher biostability, such as polycarbonate diol (Pinchuk "A review of the biostability and carcinogenity of polyurethanes in medicine and a new generation of `biostable` polyurethanes" J. Biomat. Sci. Polymer Edn., 6, (3), 225-267 (1994), M. Szycher et al. "Biostable polyurethane elastomerics", Medical Device Technology, 11, (1992), 42-51); polyethers with a higher number of CH2 groups between oxygen bridges (G. F. Meijs et Al., "Polyurethane elastomerics containing novel macrodiols I. Synthesis and properties", Trans. 4th World Biomaterials Congress, 1992, 473) and aliphatic macroglycols (A. J. Coury et Al., "Novel soft segment approaches to implantable biostable polyurethanes", Trans. 4th World Biomaterials Congress, 1992, 661) have been studied and developed. The necessity of using different macroglycols is determined by the fact that polyurethanes obtained from polyester diols or polyether diols are subjected to in-vivo degradation and this effect is determined just by the type of glycol (Stokes, P., Urbanski, K., Cabian "Polyurethanes in Biomedical Engineering, p. 109, H. Plank et al., (eds) Elsevier, Amsterdam 109 (1987), (Pinchuk "A review of the biostability and carcinogenity of polyurethanes in medicine and a new generation of `biostable` polyurethanes" J. Biomat. Sci. Polymer Edn., 6, (3), 225-267 (1994).
Polyesterurethanes suffer self-catalytic acid hydrolytic degradation (or basic, but it is an uncommon situation in physiological environment) (Amin, J. Willie, K, Shah, A. Kydonieus, J. Biomed. Mat. Res., 27, 655 (1993)), in the presence of acids, enzymes (esterases) and oxidants.
Thorough studies were carried out on the degradation of polyetherurethanes, which are hydrolytically much more stable than polyesterurethanes and are used in long term applications (W. Hergenrother, H. D. Wabers, S. L. Cooper "Effect of hard segment chemistry and strain on the stability of polyurethanes: in vivo stability", Biomat., 14, 449 (1993)).
The polyether leading to a polyurethane with the best physical properties is PTMO (or PTMEG). Polyetherurethanes prepared with this soft segment present a mechanical strength comparable to the one of polyesterurethanes and very good hydrolytic stability (D.
Lelah, S. L. Cooper, Polyurethanes in Medicine, p. 27-28, CRC Press (1986)). In the past, hydrogenated polybutadiene and polyisobutylene were also used as macroglycols, allowing the synthesis of polyurethanes with excellent resistance to light, thermal and hydrolytic degradation (Brunette, C. M. Hsu, S. L. Macnight, W. J., and Schnider, "Structural and mechanical properties of polybutadiene-containing polyurethanes", Polym. Eng. Sci., 21, 163, (1981)). Unfortunately, the synthesis of these materials is difficult and the physical properties of the resulting polymer are lower than the ones of conventional polyurethanes.
Chain extenders: diols or diamines
Chain extenders used for the production of polyurethanes with a biphasic structure and desirable physical properties have a low molecular weight with respect to macrodiisocyanate and when they react with it, they are included in the hard segment, increasing the chain molecular weight. It was demonstrated that when the chain of the extender contains an even number of carbon atoms, the hard segment crystallises easier than when the number of carbon atoms is odd, such as in the case of nylons. Generally a more rigid crystalline domain brings to a polyurethane with better physical characteristics (D. Lelah, S. L. Cooper, Polyurethanes in Medicine, p. 27-28, CRC Press (1986). Chain extenders are bifunctional and end with amino or hydroxy groups, giving rise to polyureaurethanes and polyurethanes, respectively, characterised by a different morphology and by different mechanical properties. Diamines form urea bonds, which make polyureaurethanes less soluble in the common solvents and make them more difficult to process in melting processes, such as extrusion or moulding, thus limiting their application in the production of fibres and coatings (dip-coating). Moreover, recent studies have demonstrated that polyetherureaurethanes are more sensitive to biodegradation with respect to the analogous polyetherurethane containing butandiol as chain extender (Pinchuk "A review of the biostability and carcinogenity of polyurethanes in medicine and a new generation of `biostable` polyurethanes" J. Biomat. Sci. Polymer Edn., 6, (3), 225-267 (1994)). Advantageously, polyureaurethanes, since they have stronger intermolecular bonds, have a higher fatigue resistance.
Polyurethaneamides (PUA) are poorly disclosed in literature.
Copolymers obtained from macroglycols, having diisocyanates and dicarboxylic acids as chain extenders, are an example of PUA. In this case, in the second reaction step CO2 develops, with formation of amide bonds (D. Cohn, A. Penhafi, Clinical Materials, 8, p. 105 (1991).
The tendency demonstrated by amido groups to form strong intermolecular hydrogen bonds leads to the formation of well distinct hard domains, giving the polymeric material improved mechanical properties. Further, rigidity and planarity increase, combined with amido groups, itself contributing to develop a sharper phase separation with consequent better mechanical properties, is an advantageous characteristic of these chain extenders.
For these reasons, the need to have available new polyurethaneamides using diols containing amido groups as chain extenders is still present. Said extenders, not commercially available, must be purposely synthesised.